Pleiotropic antifibrotic actions of aspirin-triggered resolvin D1 in the lungs

Introduction: Pulmonary fibrosis is a destructive, progressive disease that dramatically reduces life quality of patients, ultimately leading to death. Therapeutic regimens for pulmonary fibrosis have shown limited benefits, hence justifying the efforts to evaluate the outcome of alternative treatments. Methods: Using a mouse model of bleomycin (BLM)-induced lung fibrosis, in the current work we asked whether treatment with pro-resolution molecules, such as pro-resolving lipid mediators (SPMs) could ameliorate pulmonary fibrosis. To this end, we injected aspirin-triggered resolvin D1 (7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E19Z-docosahexaenoic acid; ATRvD1; i.v.) 7 and 10 days after BLM (intratracheal) challenge and samples were two weeks later. Results and discussion: Assessment of outcome in the lung tissues revealed that ATRvD1 partially restored lung architecture, reduced leukocyte infiltration, and inhibited formation of interstitial edema. In addition, lung tissues from BLM-induced mice treated with ATRvD1 displayed reduced levels of TNF-α, MCP-1, IL-1-β, and TGF-β. Of further interest, ATRvD1 decreased lung tissue expression of MMP-9, without affecting TIMP-1. Highlighting the beneficial effects of ATRvD1, we found reduced deposition of collagen and fibronectin in the lung tissues. Congruent with the anti-fibrotic effects that ATRvD1 exerted in lung tissues, α-SMA expression was decreased, suggesting that myofibroblast differentiation was inhibited by ATRvD1. Turning to culture systems, we next showed that ATRvD1 impaired TGF-β-induced fibroblast differentiation into myofibroblast. After showing that ATRvD1 hampered extracellular vesicles (EVs) release in the supernatants from TGF-β-stimulated cultures of mouse macrophages, we verified that ATRvD1 also inhibited the release of EVs in the bronco-alveolar lavage (BAL) fluid of BLM-induced mice. Motivated by studies showing that BLM-induced lung fibrosis is linked to angiogenesis, we asked whether ATRvD1 could blunt BLM-induced angiogenesis in the hamster cheek pouch model (HCP). Indeed, our intravital microscopy studies confirmed that ATRvD1 abrogates BLM-induced angiogenesis. Collectively, our findings suggest that treatment of pulmonary fibrosis patients with ATRvD1 deserves to be explored as a therapeutic option in the clinical setting.Fil: Guilherme, Rafael F.. Universidade Federal do Rio de Janeiro; BrasilFil: Silva, José Bruno N.F.. Universidade Federal do Rio de Janeiro; Brasil. Universidade Federal do Tocantins; BrasilFil: Waclawiack, Ingrid. Universidade Federal do Rio de Janeiro; BrasilFil: Fraga Junior, Vanderlei S.. Universidade Federal do Rio de Janeiro; BrasilFil: Nogueira, Thaís O.. Universidade Federal do Rio de Janeiro; BrasilFil: Pecli, Cyntia. Universidade Federal do Rio de Janeiro; BrasilFil: Araújo Silva, Carlla A.. Universidade Federal do Rio de Janeiro; BrasilFil: Magalhães, Nathalia S.. Ministerio de Salud de Brasil. Fundación Oswaldo Cruz. Instituto Oswaldo Cruz;Fil: Lemos, Felipe S.. Ministerio de Salud de Brasil. Fundación Oswaldo Cruz. Instituto Oswaldo Cruz;Fil: Bulant, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; ArgentinaFil: Blanco, Pablo Javier. Laboratório Nacional para Computação Científica; BrasilFil: Serra, Rafaela. Universidade Federal do Rio de Janeiro; BrasilFil: Svensjö, Erik. Universidade Federal do Rio de Janeiro; BrasilFil: Scharfstein, Júlio. Universidade Federal do Rio de Janeiro; BrasilFil: Moraes, João A.. Universidade Federal do Rio de Janeiro; BrasilFil: Canetti, Claudio. Universidade Federal do Rio de Janeiro; BrasilFil: Benjamim, Claudia F.. Universidade Federal do Rio de Janeiro; Brasi

Tomographic Imaging of the Sagittarius Spiral Arm's Magnetic Field Structure

The Galactic global magnetic field is thought to play a vital role in shaping Galactic structures such as spiral arms and giant molecular clouds. However, our knowledge of magnetic field structures in the Galactic plane at different distances is limited, as measurements used to map the magnetic field are the integrated effect along the line of sight. In this study, we present the first-ever tomographic imaging of magnetic field structures in a Galactic spiral arm. Using optical stellar polarimetry over a $17' \times 10'$ field of view, we probe the Sagittarius spiral arm. Combining these data with stellar distances from the $Gaia$ mission, we can isolate the contributions of five individual clouds along the line of sight by analyzing the polarimetry data as a function of distance. The observed clouds include a foreground cloud ($d < 200$ pc) and four clouds in the Sagittarius arm at 1.23 kpc, 1.47 kpc, 1.63 kpc, and 2.23 kpc. The column densities of these clouds range from 0.5 to $2.8 \times 10^{21}~\mathrm{cm}^{-2}$. The magnetic fields associated with each cloud show smooth spatial distributions within their observed regions on scales smaller than 10 pc and display distinct orientations. The position angles projected on the plane-of-sky, measured from the Galactic north to east, for the clouds in increasing order of distance are $135^\circ$, $46^\circ$, $58^\circ$, $150^\circ$, and $40^\circ$, with uncertainties of a few degrees. Notably, these position angles deviate significantly from the direction parallel to the Galactic plane.Comment: Accepted for publication in Ap

Mitochondrionopathy Phenotype in Doxorubicin-Treated Wistar Rats Depends on Treatment Protocol and Is Cardiac-Specific

Although doxorubicin (DOX) is a very effective antineoplastic agent, its clinical use is limited by a dose-dependent, persistent and cumulative cardiotoxicity, whose mechanism remains to be elucidated. Previous works in animal models have failed to use a multi-organ approach to demonstrate that DOX-associated toxicity is selective to the cardiac tissue. In this context, the present work aims to investigate in vivo DOX cardiac, hepatic and renal toxicity in the same animal model, with special relevance on alterations of mitochondrial bioenergetics. To this end, male Wistar rats were sub-chronically (7 wks, 2 mg/Kg) or acutely (20 mg/Kg) treated with DOX and sacrificed one week or 24 hours after the last injection, respectively. Alterations of mitochondrial bioenergetics showed treatment-dependent differences between tissues. No alterations were observed for cardiac mitochondria in the acute model but decreased ADP-stimulated respiration was detected in the sub-chronic treatment. In the acute treatment model, ADP-stimulated respiration was increased in liver and decreased in kidney mitochondria. Aconitase activity, a marker of oxidative stress, was decreased in renal mitochondria in the acute and in heart in the sub-chronic model. Interestingly, alterations of cardiac mitochondrial bioenergetics co-existed with an absence of echocardiograph, histopathological or ultra-structural alterations. Besides, no plasma markers of cardiac injury were found in any of the time points studied. The results confirm that alterations of mitochondrial function, which are more evident in the heart, are an early marker of DOX-induced toxicity, existing even in the absence of cardiac functional alterations